tbuckley/cabot-search huggingface dataset:
Abstract 2178: Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity
Authors: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis
Journal: Cancer Research (2022)

Abstract High levels of dietary fats are associated with pancreatitis, diabetes, and pancreatic cancer. Sterol regulatory element binding protein Cleavage-Activating Protein (SCAP) is an essential intermediate in lipid-regulated activation of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, which induce expression of genes regulating lipid homeostasis. We previously demonstrated that the elevated SREBP1 arising from inhibition of the cholesterol biosynthetic pathway in mice genetically predisposed to pancreatic cancer additionally transcribed genes that induced epithelial-mesenchymal transition, promoting basal rather than glandular cancer. To further evaluate SCAP and SREBP function in the pancreas, we developed a new mouse model with selective pancreatic knockout of the Scapf/f gene under the control of the Pdx1-Cre promoter (ScapΔpanc mice). Although size of the pancreas in ScapΔpanc neonates was unaffected, and number of islets was normal, there was a reduced number of acinar cells, and some evidence of disorganized tissue structure. Preliminary histopatholgical assessment of pancreatic tissue of ScapΔpanc neonates indicated no acinar cell apoptosis, and unimpaired acinar proliferation, suggesting loss of Scap may cause a differentiation defect. Further supporting this idea, siRNA depletion of Scap in the rat AR42J acinar cell line resulted in loss of markers of mature acinar cell identity. ScapΔpanc pancreata underwent progressive and selective loss of acinar cells as mice aged, with three-month old mice having large areas of acinar cell loss, and mislocalization of ductal cells. Coupled with this loss was a large increase in pancreatic adipocytes and mesenchymal cells, resulting in a highly disorganized tissue morphology accompanied by signs of inflammation. These phenotypes were exacerbated in mice maintained on high fat or high carbohydrate diet. Together, these results imply that SCAP and SREBP signaling in the pancreas plays an important role in mediating dietary modulation of pancreatic development, acinar cell homeostasis, and restraint of pancreatic adiposity. Intrapancreatic fat, associated with obesity and chronic pancreatitis, is a known risk factor for pancreatic cancer, and SCAP polymorphisms have been to interact with diet in regulating obesity and blood pressure in humans; we propose SCAP-SREBP signaling in the pancreas may mediate dietary promotion of pancreatic cancer risk. Citation Format: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis. Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2178.
Abstract 5063: Predicting target driven toxicity for small molecule inhibitors to aid in drug development
Authors: Manuel Garcia-Quismondo, Mukti Parikh, Neel Madhukar, Coryandar Gilvary
Journal: Cancer Research (2022)

Abstract Adverse events and toxicity concerns account for roughly 50% of clinical trial failures and the majority of drug withdrawals. A large part of these toxicity effects can be explained by a drug’s molecular target, known off targets or a drug’s lack of specificity. Therefore, the understanding of a target’s potential toxicity is crucial in the drug development process, potentially informing therapeutic hypotheses and/or chemical design. Here, we introduce a machine learning model to predict a gene’s likelihood to result in patient toxicity when inhibited, independent of chemical compound information. We used information on drug approvals, discontinuations and withdrawals from the FDA to define “toxic” and “safe” targets, to be used as training data. Our model leveraged preclinical, gene-specific features that can be easily collected such as tissue expression, pathway involvement, and loss of function data, and achieves significant predictive performance (ROC = 0.80). We validated our model’s ability to discriminate between successful and unsuccessful drug candidates based on their predicted target toxicity. Furthermore, our model was able to predict differences in toxicity between gene isoforms, which were in agreement with published in vivo evidence, further highlighting its ability to be applied to guide drug development and lead optimization. By applying our model, the prediction of target-specific toxicity can guide drug screenings, prioritize candidates and avoid costly and dangerous drug failures. Citation Format: Manuel Garcia-Quismondo, Mukti Parikh, Neel Madhukar, Coryandar Gilvary. Predicting target driven toxicity for small molecule inhibitors to aid in drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5063.
Abstract 3835: Kindlin-2 complexes containing α6β1 integrin are responsive to hypoxia
Authors: Daniel Hernandez-Cortes, Jaime M.C. Gard, Beatrice S. Knudsen, Noel A. Warfel, Anne E. Cress
Journal: Cancer Research (2022)

Abstract The laminin-binding integrins are mechanosensory receptors critical for cell adhesion and structural organization that link the extracellular matrix (ECM) to the cytoskeleton. Integrin α6β1 is associated with prostate cancer (PCa) migration, invasion, metastasis, and decreased cancer-specific survival. Kindlin-2 (FERMT2) is a β1 integrin adaptor and mechanosensory focal adhesion (FA) protein that activates and clusters integrins in response to structural ECM alterations in the tumor microenvironment. Our goal was to determine if integrin-kindlin-2 adhesion complexes (kindlin-2:α6β1) were responsive to hypoxia, a physiologically relevant and altered microenvironment in PCa progression. Five different endpoints were tested including the biochemical analysis of kindlin-2 complexes, qRT-PCR, immunoblotting, immunocytochemistry, and electric cell impedance sensing (ECIS). Using DU145 prostate cancer cells grown under hypoxia (1% O2) for up to 16 hours, the results showed a reversible increase in kindlin-2:α6β1 complexes with maximal assembly within 4 hours and disassembly starting by 8 hours. Notably, kindlin-2:α6β1 complexes were found exclusively within membrane projections and were not observed within hypoxia-inducible paxillin (PXN)-containing FAs. The hypoxia induced kindlin-2:α6β1 complexes and classical FAs were dependent on kindlin-2 as determined by CRISPR-Cas9 heterozygous deletion of FERMT2. Protein co-localization of α6 integrin and PXN with kindlin-2 within membrane projections and FAs, respectively, was also induced under hypoxia. Further, non-invasive ECIS measurements in live cells confirmed functional cell-cell and cell-ECM dynamics driven by hypoxia and requiring kindlin-2. Our results indicate that the kindlin-2:α6β1 complexes are uniquely associated with FA-independent membrane projections induced by hypoxia, a tumor microenvironment associated with aggressive prostate cancer. The novel kindlin-2:α6β1 complexes may represent an actionable pharmacological target for blocking escape of organ confined disease and metastasis promoting steps of human prostate cancer. (Partially supported by NIH grants CA P30 23074, DOD W81XWH-19-1-0455, and NCI R01 CA242226). Citation Format: Daniel Hernandez-Cortes, Jaime M.C. Gard, Beatrice S. Knudsen, Noel A. Warfel, Anne E. Cress. Kindlin-2 complexes containing α6β1 integrin are responsive to hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3835.
Abstract 2977: Profiling oncogenic Ras mutant drugs with homogeneous bioluminescent immunoassays
Authors: Hicham Zegzouti, Laurie Engel, Matthew Swiatnicki, Juliano Alves, Said A. Goueli
Journal: Cancer Research (2022)

Abstract Activating KRAS mutations present in many cancers are difficult to target with drugs until recently with the FDA approval of sotorasib (AMG-510), a KRAS G12C selective inhibitor. In an effort to study Ras inhibitors in cells and identify new compounds that inhibit Ras and its downstream signaling, assays such as western or ELISA are commonly used. These traditional immunoassays can be tedious, require multiple washing steps, and are not easily adaptable to a high throughput screening (HTS) format. To overcome these limitations, we developed Lumit, a novel immunoassay approach that combines bioluminescent enzyme subunit complementation technology and immunodetection. We applied this bioluminescent and homogeneous “Add and Read” assay to analyze Ras signaling pathway activation and inhibition through multiple nodes of the pathway including detection of phosphorylated ERK. The assay was used to profile different allele specific inhibitors with cell lines harboring different activating KRAS mutations and obtained the predicted pharmacology and selectivity. The potency of PROTAC compound targeting selective degradation of KRAS G12C was also tested using Lumit and the result showed that maximal decrease in RAS signaling was achieved. Unlike current assays that require lengthy sample preparation and multiple washing steps, the Lumit immunoassay provides an alternative platform because it is homogeneous and allows to decipher signaling pathways activities in a fast and simple manner. Our results demonstrate that this bioluminescent technology can be adapted to any signaling pathway node, allowing scientists to streamline the analysis of signaling pathways of interest such as Ras, and identify much needed inhibitors of its mutants. Citation Format: Hicham Zegzouti, Laurie Engel, Matthew Swiatnicki, Juliano Alves, Said A. Goueli. Profiling oncogenic Ras mutant drugs with homogeneous bioluminescent immunoassays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2977.
Abstract 2151: Identification and proteogenomic characterization of novel lung adenocarcinoma subtypes with therapeutic relevance
Authors: Whijae Roh, Yifat Geffen, Mendy Miller, Shankara Anand, Jaegil Kim, David Heiman, Matthew Meyerson, Peter Laird, Andrew Cherniack, Gad Getz
Journal: Cancer Research (2022)

Abstract Lung adenocarcinoma (LUAD) is one of the most common cancer types with various available treatment modalities. However, better biomarkers of response are still needed for further improving precision medicine. Therefore, a robust LUAD subtyping can substantially aid in determining the most effective therapies that target subtype-specific vulnerabilities. In this study, we integrated multiple datasets: (i) the full 509 LUAD patient cohort from The Cancer Genome Atlas (TCGA) project, (ii) cancer vulnerability data in LUAD cell lines from the Broad Institute’s DependencyMap, and (iii) proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) LUAD patients. Using these datasets, we identified 5 expression subtypes (S1-S5) with unique proteogenomic and dependency profiles that increased the resolution of previously defined subtypes (Proximal Inflammatory [PI]; Proximal Proliferative [PP]; and Terminal Respiratory Unit [TRU]). S4-associated cell lines exhibited specific vulnerability to CDK6 and CDK6-cyclin D3 complex gene, CCND3. S3 was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, which also led to increased PD-L1 expression. Finally, we identified a small set of biomarkers for S3 and S4 that could be used in the clinic to classify patients into our therapeutically relevant subtypes. Overall, our lung adenocarcinoma expression subtypes, especially S3 that represents 20% of LUAD patients and S4 that represents 25% of LUAD patients, and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome. Citation Format: Whijae Roh, Yifat Geffen, Mendy Miller, Shankara Anand, Jaegil Kim, David Heiman, Matthew Meyerson, Peter Laird, Andrew Cherniack, NCI CCG Tumor Molecular Pathology (TMP) Analysis Working Group, Gad Getz. Identification and proteogenomic characterization of novel lung adenocarcinoma subtypes with therapeutic relevance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2151.
Abstract 1009: A novel C-terminal HSP90 inhibitor NCT-58 targets cancer stem-like properties and suppresses migratory ability in triple-negative breast cancer cells
Authors: Soeun Park, Jung Min Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2022)

Abstract Background: Although several N-terminal HSP90 inhibitors have been investigated in clinical trials, none have yet been approved for clinical use due to issues including induction of the heat shock response (HSR), off-target effects and toxicity. A major issue for N-terminal inhibitors is induction of the heat shock response (HSR) which triggers cell survival. In the present study, we investigated the effects of NCT-58, a rationally-designed novel HSP90 inhibitor that instead targets the C-terminal domain, and evaluated its capacity to induce apoptosis and target cancer stem-like properties in triple-negative breast cancer. Materials and Methods: The effect of NCT-58 on TNBC cell lines in vitro was evaluated with cell viability, apoptosis, heat shock response and cell migration. Cancer stem-like properties were examined by Aldefluor positivity, CD44+/CD24- stem-like population and mammosphere formation assays. Results: NCT-58 induces apoptosis in TNBC cells without triggering the heat shock response (HSR) due to its targeting of the C-terminal region. This is accompanied by potent and simultaneous degradation of AKT, MEK and STAT3. Importantly, NCT-58 kills not only the rapidly proliferating tumor cells and but also effectively eradicates the breast cancer stem-like population (BCSCs). The latter phenomena are accompanied by reductions in the activity of stem/progenitor marker ALDH1 and the CD44+/CD24- stem-like population and as well as impairment of mammosphere formation. Furthermore, NCT-58 markedly impairs cell migratory ability, coinciding with collapse of HSP90 client cytoskeletal proteins including vimentin and F-actin in TNBC cells in vitro. It is noteworthy that NCT-58 exhibits more cytotoxic to tumor cells but minimally cytotoxicity to non-malignant cells. Conclusion: These findings suggest that NCT-58 may represent an effective therapeutic approach for the simultaneous targeting of HSP90 and its client oncoproteins for the treatment of molecularly heterogeneous TNBC. Citation Format: Soeun Park, Jung Min Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. A novel C-terminal HSP90 inhibitor NCT-58 targets cancer stem-like properties and suppresses migratory ability in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1009.
Abstract 5709: Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer
Authors: ranran kong, Ayushi S. Patel, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Yang Tian, Feng Jiang, Charles A. Powell, Eric Snyder, Jiantao Jiang, Shaomin Li, Hideo Watanabe
Journal: Cancer Research (2022)

Abstract Introduction: The current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors, SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3), and SCLC-Y (YAP1) still leaves its major subtype SCLC-A as a large heterogeneous group, necessitating more precise characterization of lineage subclasses. Experimental procedure: To refine the current SCLC classification and to identify specific lineage features of the SCLC subtypes, we performed unsupervised hierarchical clustering of H3K27ac profiles on transcriptional regulators from 25 SCLC cell lines and determined the epigenomic features for each cluster. Functional significance of the transcriptional lineage regulators for the identified cluster was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined to reveal their functional output in the identified subtype. Rb1fl/flTrp53fl/fl and Rb1fl/flTrp53fl/flNkx2-1fl/fl genetic engineered mouse model were generated to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were further analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes. Summary: We identified previously uncharacterized epigenomic sub-clusters of the major SCLC-A subtype, named SCLC-A1 and SCLC-A2. SCLC-A1 was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-A1, where it maintains neural lineage rather than pulmonary epithelial identity. We further found maintenance of this neural identity in SCLC-A1 is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. ? Conclusions: We comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A1 subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain a neuronal linage state. Citation Format: ranran kong, Ayushi S. Patel, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Yang Tian, Feng Jiang, Charles A. Powell, Eric Snyder, Jiantao Jiang, Shaomin Li, Hideo Watanabe. Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5709.
Phenotype, Function, and Clinical Significance of CD26+ and CD161+Tregs in Splenic Marginal Zone Lymphoma
Authors: Xinyi Tang, Zhi-Zhang Yang, Hyo Jin Kim, Theodora Anagnostou, Yue Yu, Xiaosheng Wu, Jun Chen, Jordan E. Krull, Kerstin Wenzl, Patrizia Mondello, Vaishali Bhardwaj, Junwen Wang, Anne J. Novak, Stephen M. Ansell
Journal: Clinical Cancer Research (2022)

Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied.Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays.We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition.IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
Abstract 3195: Tumor inhibitory CAFs in CNS metastases
Authors: Thomas Simon, David Buckley, Bodour Salhia
Journal: Cancer Research (2022)

Abstract The 2-year survival rate for patients with central nervous system (CNS) metastases (CMs) remains below 2%. With the aim to define new therapeutic options, researchers have investigated how interactions between CM cells and the surrounding tumor microenvironment (TME) support metastatic progression. As an important component of the TME, cancer associated fibroblasts (CAFs) have largely been reported as tumor supportive. But new evidence for the high heterogeneity of the CAF compartment, including in vivo studies from our lab, showed that certain CAF subpopulations could exhibit tumor inhibitory capabilities. Interestingly, recent reports revealed that CAFs showing high expression of Immunoglobulin Superfamily containing Leucin Rich Repeat (ISLR) could show tumor inhibitory capabilities in both pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Yet, despite the invaluable clinical potential of tumor inhibitory CAFs, the CAF compartment in the TME of CMs is still largely under described. Using CM patient tissue and CM patient-derived cell lines established in our lab, we performed single cell RNA sequencing (scRNA-seq) to define CAF subpopulations present in the TME of CMs. We identified distinct clusters characterized by differential expression of ISLR and tumor supportive CAF marker Actin Alpha 2, Smooth Muscle (ACTA2/α-SMA). CAF subpopulations were thus defined as follows: ISLRhigh/α-SMAlow, ISLRlow/α-SMAhigh, ISLRlow/α-SMAlow. Altogether, we hypothesized that ISLRhigh/α-SMAlow CAFs could act to restrain tumor progression in the TME of CMs, as opposed to potentially tumor supportive ISLRlow/α-SMAhighCAFs. ISLRhigh and ISLRlow CAFs were obtained through fluorescence-activated cell sorting (FACS) performed on one of our patient-derived CAF cell lines represented in all defined scRNA-seq clusters. ISLRhigh CAFs were validated to express lower levels of α-SMA (ISLRhigh/α-SMAlow CAFs) compared to ISLRlow cells (ISLRlow/α-SMAhigh CAFs). This mutually exclusive expression of ISLR and α-SMA in different CAF subpopulations is in accordance with recent data in PDAC and CRC and could indicate common underlying mechanisms driving the phenotype of each subpopulation. Further in vitro and in vivo experiments are currently underway in our lab to determine the tumor supportive capabilities of both ISLRhigh/α-SMAlow and ISLRlow/α-SMAhigh CAFs. Ultimately, we expect the current study to unravel the diverse and dynamic nature of CAFs in the TME of CMs, which is still largely unknown. Citation Format: Thomas Simon, David Buckley, Bodour Salhia. Tumor inhibitory CAFs in CNS metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3195.